One gene with a domino effect on social behavior


TTranscription factors that coordinate the expression of multiple genes may play important roles in controlling behavior, but scientists need to explore them. Peter Hamilton, a neuroscientist at Virginia Commonwealth University, has contributed to this research for many years, particularly in the context of social behavior research. In 2019, he and his colleagues identified transcription factors (TFs) that correlate with stress tolerance in rodents.1 In a recent study, Hamilton and his team found that the same TF modulates social behavior in mice, unexpectedly linking the brain and immune system.2 Their discovery is translational psychiatryshed light on the genetics that underpin social behavior in mammals and laid the foundation for identifying genes that contribute to mental illness.

The neuromodulators that Hamilton identified in his initial studies belong to the largest family of TFs in mammals, called Kruppel-associated box (KRAB) zinc finger proteins (ZFPs).3 Its members directly control genes and repress transposable elements, which are DNA sequences that control other genes.4,5 In the new study, Hamilton and his team investigated how the TF in question, ZFP189, affects stress in mice by creating a synthetic version with inverted function. They replaced its repressive domain with an activator to destroy the repressive effect on the transposable element. The researchers then gave the mice additional copies. ZFP189 genes, either synthetic or regular versions. “There may be a sweet spot for controlling transposable elements: too much or too little. [ZFP189] It can lead to dysregulation of social behavior,” Hamilton explained.

They could quickly see that the synthetic TFs disrupted neuronal physiology. Neurons in the prefrontal cortex, a brain region sensitive to stress and important for cognition, mushroomed more in mice given synthetic activating TF compared to mice given the inhibitory form.6

Next, to see how these perturbations affected stress tolerance in mice, the researchers placed mice given synthetic ZFP189 in cages with larger, more aggressive mice. I did.7 Mice can usually tolerate some hostility, but Hamilton noticed that these mice behaved differently. This led him to suggest that ZFP189 not only influences stress responses, but may also influence social behavior more broadly.

Curious about the extent to which ZFP189 influences group dynamics, his team conducted a social dominance tube test to see whether mice fed synthetic TFs were able to recognize social hierarchy.8 They placed two mice facing each other at the end of a tube that was too thin for either to turn around. Under normal circumstances, the dominant mouse usually moves forward and the subordinate mouse moves backwards. “But when we introduced a synthetic transcription factor, all bets were off and its performance was just a coincidence,” Hamilton said.

Mice carrying synthetic TF moved forward half the time and backward half the time, regardless of the social ladder. This suggests that they were unable to perceive it. “This indicates that this transcription factor promotes brain functions necessary for social cognition,” Hamilton noted.

After finding that this TF controls more cognitive functions than expected, the research team used RNA-seq to examine how the synthetic TF affected the transcriptome of neurons in the prefrontal cortex. I looked at the decision. The researchers thought that the modified ZFP189 activated hundreds of transposable elements, which could cause a domino effect on gene regulation. Further investigation revealed that while the awakened transposable element shuts down a range of immune genes, the normal version of ZFP189 turns on these immune factors.

Neuroscientists were puzzled to discover that ZFP189 normally activates immune genes. Because the brain is an immunoprivileged organ, with physical fortifications that protect against pathogen invasion and, as a result, requires less immune surveillance, the researchers are interested in understanding how these immune factors work in the prefrontal cortex. I didn't know what they were doing.9 Previously, scientists have suggested that inflammation can cause individuals to withdraw from social situations to limit the spread of infection, and that these immune genes may contribute to reclusive behavior during illness. It has been hypothesized that this may promoteTen

“The trend in neuroscience is that the immune system and the brain are closely linked,” says Didier Tronot, a molecular geneticist at the Swiss Federal Institute of Technology Lausanne who studies KRAB ZFP. is not involved. “In fact, what appears to be a master regulator of some neurological functions also appears to be an important regulator of some immune functions,” he added, raising the possibility that they may be physiologically linked. suggested. Alternatively, Hamilton speculated that these immune factors could be repurposed for other, unrelated functions in the brain.

The role of ZFP189 in humans remains largely unknown. “Although this study was done in mice, it is particularly interesting because there is a human ortholog of KRAB ZFP,” he said.

Next, Hamilton plans to investigate the role of this TF in neuropsychiatric disorders. “It would be great if this transposable element mechanism could explain some of the social deficits that are common to so many brain diseases,” he says.

References

1. Lorsch ZS et al. Stress resilience is promoted by his Zfp189-driven transcriptional network in the prefrontal cortex. nut neurosi. 2019;22(9):1413-1423.
2. Truby NL and other zinc finger transcription factors enable social behavior while regulating transposable elements and immune responses in the prefrontal cortex. trans psychiatry. 2024;14(1):59.
3. Playfoot CJ and its other transposable elements and their KZFP controllers are driving forces of transcriptional innovation in the developing human brain. Genome analysis. 2021;31(9):1531-1545.
4. Yang P, et al. Role of KRAB-ZFP in transposable element repression and mammalian evolution. Trend Genet. 2017;33(11):871-881.
5. Fueyo R Role of transposable elements in transcriptional regulation in other mammals. Nat Rev Mol Cell Biol. 2022;23(7):481-497.
6. Arnsten AFT. Stress signaling pathways impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10(6):410-422.
7. Lyons DM, et al. Ecological validity of social defeat stressors in mouse models of vulnerability and resilience. Neurosci Biobehav Rev. 2023;145:105032.
8. Fulenwider HD, et al. Expression of dominance: Assessment of social dominance in rodents. Genetic brain behavior. 2022;21(3):e12731.
9. Roubaud A, et al. Reconsidering the mechanisms of CNS immune privilege. Trend Immunol. 2015;36(10):569-577.
10. Muscatel KA, Inagaki TK. Beyond social withdrawal: A new perspective on the impact of inflammation on social behavior. Behavioral immunity in the brain. 2021;16:100302.



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